Any scission into the human body is detrimental to the human body and invariably results in cell loss. The need to keep cell loss to a minimum is particularly crucial during any surgical procedure performed on delicate and irreplaceable tissues, such as the tissues of the eye, nerves, etc.
The cornea of the eye is comprised of five layers: epithelium, Bowman's membrane, stroma, Decemet's membrane, and endothelium. The endothelium layer is particularly vulnerable to trauma as the endothelial cells are infrequently, if ever, replaced as a normal process in the adult life. The endothelium is principally responsible for the maintenance of the proper state of hydration of the stromal layer. The stromal layer has a tendency to imbibe fluid, a tendency which is counterbalanced by outward fluid transport via the endothelium. If the proper fluid balance is not maintained in the stromal layer, the cornea thickens and the characteristic transparency of the cornea is lost. Accordingly, cell loss or damage in the endothelial layer will result in decreased vision. Failure of the endothelium to perform its fluid transport function for short periods of time will result in corneal thickening and visual clouding. Because of the importance of, and the vulnerability of, the endothelial layer, it is necessary during eye surgery, such as cataract and retinal surgery or corneal transplants, to make provisions for the protection of the endothelial cells.
A significant factor causing cell loss during tissue scission is the traumatic change in environment experienced by the internal cells. Exposure to the atmosphere presents a far different environment for the cells than is provided by the natural fluids in which they are bathed. To simulate the natural cellular environment and thereby prevent cell damage, exposed tissue during surgery is frequently irrigated in solutions which attempt to approximate natural body fluids. The value of bathing eye tissue during surgery to prevent cell damage has long been recognized. For internal ocular tissues, such as the endothelium, the aqueous humor is the natural bathing fluid and, hence, an ophthalmic irrigating solution to protect the endothelium should as closely as possible resemble the aqueous humor.
Of primary concern in a tissue irrigating solution is that the osmolality of the solution be generally isotonic with cellular fluids so as to maintain equal osmotic pressure within and without the cell membranes. To this end, one of the early ophthalmic irrigating solutions was isotonic (0.9%) saline. However, as has long been recognized, isotonic saline is quite inadequate as an opthalmic irrigating solution and has been shown to result in endothelial cell swelling, cell damage, and consequent corneal clouding.
Because of the inadequacy of isotonic saline, various alternative electrolyte solutions have been proposed as ophthalmic irrigating solutions in attempts to provide solutions which more closely resemble the aqueous humor and prevent cell damage and corneal clouding. Standard electrolyte solutions primarily intended for injection solutions, such as Ringer's solution and lactated Ringer's solution, have been used as ophthalmic irrigating solutions because of their wide availability as sterile solutions.
A solution intended for ophthalmic irrigation known as balanced salt solution (BSS) has also been developed. BSS contains the essential ions, calcium, sodium, potassium, magnesium and chloride in generally optimal concentrations for ocular tissue, and has an acetate-citrate buffer system which is compatible with divalent calcium and magnesium ions.
The various electrolyte solutions used for ophthalmic irrigation have been improvements over normal saline by providing necessary ions in addition to Na.sup.+ and Cl.sup.- as provided by isotonic saline. Mg.sup.++ is an important cofactor for adenosine triphosphatase, an enzyme which plays an important role in mediating the fluid transport pump in the eye. Ca.sup.++ is necessary to maintain the endothelial junction. K.sup.+ is an important factor in many biochemical processes, and the fluid transport pump of the endothelium requires a proper Na.sup.+ /K.sup.+ ratio. The previously known electrolyte solutions used to irrigate ocular tissue have reduced but not eliminated corneal swelling and cell damage.
The need for improved ophthalmic irrigating solutions continues, particularly in view of new surgical techniques which may probe deeper into the eye and require several hours of operating time. Surgical advances now permit surgery in the vitreous (posterior) chamber to remove opacified vitreous humor or to repair retinal detachment. Such operations require significant time, e.g., 1 to 3 hours, and large volumes of irrigating solution, e.g., 100-1000 ml.
During eye surgery and particularly during surgery which requires extended periods of time, proper electrolytic balance alone is insufficient to retain normal corneal thickness. To maintain proper corneal thickness and prevent cell damage, an irrigating solution in addition to electrolytic balance must provide metabolic support and must particularly provide factors needed for the enzyme-mediated Na.sup.+ /K.sup.+ pump system through which excess fluid is removed from the stroma.
To incorporate factors necessary for sustained metabolism by endothelial cells, glutathione-bicarbonate-Ringers solution (GBR) was developed in which NaHCO.sub.3, glutathione, dextrose and adenosine (an optional ingredient) are added to Ringer's solution. Bicarbonate, dextrose and glutathione have been shown to be important factors in maintaining structural integrity of endothelial cells. The aqueous humor has a bicarbonate buffer system. Dextrose (d-glucose) provides a substrate for various metabolic pathways, and glutathione has been shown to aid the metabolic pump mechanism by maintaining proper Na.sup.+ /K.sup.+ adenosine-triphosphatase. GBR has been shown effective in maintaining corneal thickness and endothelial cell integrity for up to three hours.
While the effectiveness of a GBR ocular irrigating solution has been shown both in vivo and in vitro, its use in surgery has been limited for reasons of stability and sterility. It is to be appreciated that sterility of an ophthalmic irrigating solution is absolutely essential. To insure sterility, it is desirable that an irrigating solution be prepackaged so that the quality and sterility may be closely monitored and tested as contrasted with an extemporaneously mixed solution as might be prepared in a hospital pharmacy. The solution will perfuse the eye in essentially a closed system where even a small number of organisms could produce an overwhelming endophthalmitis, as pseudomonas is one of the very few organisms that has very few metabolic requirements and can grow with a minimal nutrient supply such as phosphate and bicarbonate. Dr. Jan Worst has reported on a series of infections in Europe with pseudomonas-contaminated irrigating solutions. (January 1978, American Intraocular Implant Society Journal).
GBR may not be prepackaged due to the long term incompatability and/or instability of its various moieties. Of the moieties added to Ringer's solution to formulate GBR, bicarbonate is perhaps the most important (McEnerney et al. Investigative Ophthamology and Visual Science 16 No. 7, July 1977). Unfortunately the bicarbonate as well as the phosphate in a bicarbonate-phosphate buffer system form insoluble precipitates with Mg.sup.++ and Ca.sup.++. While at the ionic concentrations useful in ophthalmic irrigation, precipitation is not a problem in freshly prepared solution, long-term storage is proscribed. As insoluble crystals introduced into the eye will cloud vision, the importance of keeping a tissue irrigating solution free of insoluble precipitates may be readily appreciated. A Ringer's solution fortified with sodium bicarbonate and dextrose and injected in an Ocutome.RTM. Fragmatome.TM. instrument deposits pure crystals of calcium bicarbonate in the instrument system. Similar crystals are deposited during surgery inside the eye on the retina, vitreous disk, iris and on exposed uvea or sclera. (Dr. Connor O'Malley, "Salt Contamination of the Eye--An Infusion Hazard". Ocutome/Fragmatome Newsletter, 4, No. 4, 1979).
Complicating the maintenance of GBR's stability is the fact that the pH of GBR will gradually increase due to the inadequacy of the bicarbonate-phosphate buffer. To provide proper pH, i.e., about 7.4, the pH must be monitored and adjusted with CO.sub.2 immediately prior to use and even during use. The chances for contamination during pH adjustment are great.
A further factor which proscribes long-term storage of GBR is the unavailability of a proper pH at which all of the moieties are stable. Several moieties of GBR are unstable at the physiological pH of about 7.4. Below a pH of about 8, bicarbonate generally decomposes to CO.sub.2, resulting both in a loss of bicarbonate concentration and increased pH. On the other hand, glucose stability requires a pH of less than about 6. Glutathione, while biologically effective either in reduced or oxidized form, is preferred in the oxidized form because the reduced form quickly oxidizes in aqueous solutions, preventing proper labeling of the irrigating solution. Oxidized glutathione (glutathione disulfide) is unstable over extended periods of time at a pH of above about 5. The concentration of glutathione may also decrease to an unacceptable concentration when stored over long periods of time in admixture with all other components. Because of the demonstrated efficacy of GBR as an ocular irrigating solution, it would be desirable to provide a formulation which contains the essential factors found in GBR and which may be stored in a sterilized form for use in eye surgery.
Accordingly, it is a primary object of the invention to provide a stable sterile ophthalmic irrigating solution which, in addition to correct electrolyte balance, provides factors necessary for continued metabolism in the endothelial cells, maintenance of the fluid transport pump system, and consequential maintenance of proper corneal thickness and clarity.
Neurosurgery is another important area where there is a need for irrigating solutions which better stabilize irreplaceable tissue. It is well known that destroyed nerve cells, for the most part, are not regenerated. Normal saline is the traditional wound irrigating solution used in neurosurgery, at least partially because of its low cost and ready availability. However, the use of saline has several theoretical disadvantages which may be of unrecognized clinical importance. The pH of saline ranges from 5-7 and is unbuffered; therefore, it causes an acid environment. In the absence of circulating cerebrospinal fluid, as is usually the case in open neurosurgical procedures, this acid pH may cause damage to the exposed brain and spinal cord.
It is another primary object of the present invention to provide an irrigating solution that stabilizes neuro tissue and other sensitive tissues.